IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration

Liver regeneration is a tightly regulated process requiring coordinated interactions between hepatocytes and non-parenchymal cells; however, its molecular mechanisms remain incompletely defined. Here, we aimed to investigate the role of interferon-related developmental regulator 1 (IFRD1) in regulating metabolic-immune crosstalk during liver regeneration.

We integrated public transcriptomic datasets, human liver disease samples, and multiple in-house-generated experimental models to characterize the dynamic expression of IFRD1 during liver regeneration. Genetic loss-of-function approaches, including global and cell type-specific knockout mice, together with adeno-associated virus-mediated gain-of-function strategies, were combined with single-nucleus RNA-seq, ATAC-seq, metabolic and biochemical assays, protein interaction analyses, and in vivo rescue experiments.

Hepatocyte IFRD1 was rapidly induced during the early phase of liver regeneration in mice but markedly diminished in human chronic liver disease. Hepatocyte-specific loss of IFRD1 impaired liver repair and regeneration, whereas IFRD1 overexpression enhanced regenerative responses across multiple models, including partial hepatectomy, toxic liver injury, and hepatic ischemia-reperfusion injury. Mechanistically, IFRD1 was required to sustain hepatocyte β-oxidation and mitochondrial ATP production by stabilizing SLC25A5 through competition with the E3 ubiquitin ligase TRIM21. This ATP boost enables chromatin remodeling in hepatocytes, promoting CCL/CXC chemokine expression to recruit CCR2⁺ monocytes and expand the regenerative GPNMB⁺ macrophage pool. Notably, IFRD1 overexpression restored liver regenerative capacity after partial hepatectomy in mice with metabolic dysfunction-associated steatohepatitis or diethylnitrosamine-induced liver fibrosis.

Our findings define IFRD1 as a key immunometabolic regulator of liver regeneration, linking hepatocyte metabolic control to macrophage-driven regenerative responses. These results support the therapeutic potential of targeting IFRD1 to enhance regenerative capacity in liver disease.

Liver regeneration is essential for recovery from surgical resection and acute injury, yet therapeutic options to enhance this process remain limited. Our study identifies the IFRD1-SLC25A5-ATP axis as a critical regulator that links hepatocyte energy metabolism with the expansion of a pro-regenerative macrophage pool. This previously unrecognized regulatory node provides a scientific rationale for developing therapeutic strategies that enhance IFRD1 function to accelerate liver repair. While upstream regulators of IFRD1 remain undefined, these findings lay a foundation for improving regenerative outcomes in patients with compromised liver function.